Inhibition of MBTPS1 reprograms cold into inflamed tumors and potentiates anti-PD-1 immunotherapy [scRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1097966 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28596298_1.fastq.gz | Fastqsanger.gz | |||
| SRR28596298_2.fastq.gz | Fastqsanger.gz | |||
| SRR28596299_1.fastq.gz | Fastqsanger.gz | |||
| SRR28596299_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 4 of 4 |
Similar Datasets
Project description:Inhibition of MBTPS1 reprograms cold into inflamed tumors and potentiates anti-PD-1 immunotherapy
| PRJNA1094412 | ENA
Project description:Despite notable advancements in cancer immunotherapy, the overall response rate among cancer patients remains low. Therefore, exploring strategies combining immunotherapy with adjuvant approaches to augment adaptive immune responses, such as by boosting the infiltration of T lymphocytes, is an attractive strategy. To pinpoint key regulators of tumor immunity, we developed a focused single guide RNA (sgRNA) library targeting membrane and secreted protein genes. Utilizing this library, we conducted an in vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screen in colorectal cancer mice model. We revealed that the loss of MBTPS1 in tumor cells enhanced anti-tumor immunity and synergized with anti-PD-1 therapy. Mechanistic studies uncovered that tumor cell-intrinsic MBTPS1 could compete with USP13 for binding with STAT1, thereby disrupting the USP13-dependent deubiquitination and stabilization of STAT1. MBTPS1 deficiency induced CXCR3+ CD8+ T cells infiltration in the tumor microenvironment by upregulating mRNA levels of Cxcl9, Cxcl10 and Cxcl11 transcribed by STAT1. Our study revealed that targeting MBTPS1 in cancer cells could turn cold tumors into inflamed ones, thereby enhancing the efficacy of anti-PD-1 blockade.
2025-03-14 | GSE262868 | GEO
Project description:Despite notable advancements in cancer immunotherapy, the overall response rate among cancer patients remains low. Therefore, exploring strategies combining immunotherapy with adjuvant approaches to augment adaptive immune responses, such as by boosting the infiltration of T lymphocytes, is an attractive strategy. To pinpoint key regulators of tumor immunity, we developed a focused single guide RNA (sgRNA) library targeting membrane and secreted protein genes. Utilizing this library, we conducted an in vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screen in colorectal cancer mice model. We revealed that the loss of MBTPS1 in tumor cells enhanced anti-tumor immunity and synergized with anti-PD-1 therapy. Mechanistic studies uncovered that tumor cell-intrinsic MBTPS1 could compete with USP13 for binding with STAT1, thereby disrupting the USP13-dependent deubiquitination and stabilization of STAT1. MBTPS1 deficiency induced CXCR3+ CD8+ T cells infiltration in the tumor microenvironment by upregulating mRNA levels of Cxcl9, Cxcl10 and Cxcl11 transcribed by STAT1. Our study revealed that targeting MBTPS1 in cancer cells could turn cold tumors into inflamed ones, thereby enhancing the efficacy of anti-PD-1 blockade.
2025-03-14 | GSE263524 | GEO
Project description:In this project, we transfected MC38 cells with Flag-tagged Mbtps1 or vector control. After that, we performed immunoprecipitation–mass spectrometry analysis to search the interacting proteins of MBTPS1. In our study, We observed that the loss of membrane-bound transcription factor site-1 protease (MBTPS1) in tumor cells enhanced antitumor immunity and potentiated anti-PD-1 therapy. Mechanistic studies revealed that tumor cell-intrinsic MBTPS1 competed with USP13 for binding to STAT1, thereby disrupting USP13-dependent deubiquitination and stabilization of STAT1. MBTPS1 deficiency induced CXCR3+ CD8+ T cell infiltration by upregulating STAT1-transcribed chemokines including CXCL9, CXCL10 and CXCL11. Notably, the regulatory role of MBTPS1 in antitumor immunity operates independently of its classic function in cleaving membrane-bound transcription factors. Collectively, our results provide a theoretical basis for MBTPS1 as a potential immunotherapy target and also as a predictor of immunotherapy efficacy.
2025-04-11 | PXD053978 | Pride
Project description:One of the major challenges limiting the efficacy of anti-PD-1/PD-L1 therapy in nonresponding patients is the failure of T cells to penetrate the tumor microenvironment. We showed that genetic or pharmacological inhibition of Vps34 kinase activity using SB02024 or SAR405 (Vps34i) decreased the tumor growth and improved mice survival in multiple tumor models by inducing an infiltration of NK, CD8+, and CD4+ T effector cells in melanoma and CRC tumors. Such infiltration resulted in the establishment of a T cell-inflamed tumor microenvironment, characterized by the up-regulation of pro-inflammatory chemokines and cytokines, CCL5, CXCL10, and IFNγ. Vps34i treatment induced STAT1 and IRF7, involved in the up-regulation of CCL5 and CXCL10. Combining Vps34i improved the therapeutic benefit of anti-PD-L1/PD-1 in melanoma and CRC and prolonged mice survival. Our study revealed that targeting Vps34 turns cold into hot inflamed tumors, thus enhancing the efficacy of anti-PD-L1/PD-1 blockade.
| S-EPMC7190323 | biostudies-literature
Project description:BackgroundThe main challenge against patients with cancer to derive benefits from immune checkpoint inhibitors targeting PD-1/PD-L1 appears to be the immunosuppressive tumor microenvironment (TME), in which IL-33/ST2 signal fulfills critical functions. However, whether IL-33 limits the therapeutic efficacy of anti-PD-L1 remains uncertain.MethodsMolecular mechanisms of IL-33/ST2 signal on anti-PD-L1 treatment lewis lung carcinoma tumor model were assessed by RNA-seq, ELISA, WB and immunofluorescence (IF). A sST2-Fc fusion protein was constructed for targeting IL-33 and combined with anti-PD-L1 antibody for immunotherapy in colon and lung tumor models. On this basis, bifunctional fusion proteins were generated for PD-L1-targeted blocking of IL-33 in tumors. The underlying mechanisms of dual targeting of IL-33 and PD-L1 revealed by RNA-seq, scRNA-seq, FACS, IF and WB.ResultsAfter anti-PD-L1 administration, tumor-infiltrating ST2+ regulatory T cells (Tregs) were elevated. Blocking IL-33/ST2 signal with sST2-Fc fusion protein potentiated antitumor efficacy of PD-L1 antibody by enhancing T cell responses in tumor models. Bifunctional fusion protein anti-PD-L1-sST2 exhibited enhanced antitumor efficacy compared with combination therapy, not only inhibited tumor progression and extended the survival, but also provided long-term protective antitumor immunity. Mechanistically, the superior antitumor activity of targeting IL-33 and PD-L1 originated from reducing immunosuppressive factors, such as Tregs and exhausted CD8+ T cells while increasing tumor-infiltrating cytotoxic T lymphocyte cells.ConclusionsIn this study, we demonstrated that IL-33/ST2 was involved in the immunosuppression mechanism of PD-L1 antibody therapy, and blockade by sST2-Fc or anti-PD-L1-sST2 could remodel the inflammatory TME and induce potent antitumor effect, highlighting the potential therapeutic strategies for the tumor treatment by simultaneously targeting IL-33 and PD-L1.
| S-EPMC11409265 | biostudies-literature
Project description:Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15-25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8+ T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy.
| S-EPMC8971425 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE40471: Maternal slimming reprograms metabolic gene expression in mice offspring (NimbleGen expression) GSE40477: Maternal slimming reprograms metabolic gene expression in mice offspring (NimbleGen methylation) GSE40478: Maternal slimming reprograms metabolic gene expression in mice offspring (mRNA-Seq) Refer to individual Series
2012-08-30 | E-GEOD-40479 | biostudies-arrayexpress
Project description:Patient-derived intestinal organoids provide an excellent tool to unravel mechanisms underlying ulcerative colitis (UC). Fresh biopsies, to isolate crypts and culture organoids, were obtained from both inflamed and non-inflamed regions from eight patients with active UC (Mayo endoscopic subscore ≥2), and from eight non-IBD controls.To address the inflammatory character of ex vivo organoids, we compared the transcriptome of biopsies, crypts and organoids derived from inflamed, and non-inflamed regions and aimed to (re-)induce inflammation ex vivo.
2020-10-08 | E-MTAB-7860 | biostudies-arrayexpress
Project description:Cryo-thermal therapy reprograms myeloid cells into CCL5+ mature phenotype to increase T cell infiltration and potentiates anti-PD-1 therapy
| PRJNA1392186 | ENA